1. Met and the epidermal growth factor receptor act cooperatively to regulate final nephron number and maintain collecting duct morphology
- Author
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Shuta Ishibe, Snorri S. Thorgeirsson, Roland Schmitt, Hong Ma, Arnaud Marlier, Michael Kashgarian, Anil Karihaloo, Junhui Zhang, David S. Geller, Jan Czyczk, Akashi Togawa, Mitchihiro Mitobe, and Lloyd G. Cantley
- Subjects
Male ,medicine.medical_specialty ,Receptor expression ,Kidney development ,Nephron ,Biology ,Kidney ,Mice ,Pregnancy ,Internal medicine ,medicine ,Animals ,Epidermal growth factor receptor ,RNA, Messenger ,Renal Insufficiency ,Kidney Tubules, Collecting ,Receptor ,Molecular Biology ,DNA Primers ,Mice, Knockout ,Base Sequence ,urogenital system ,Nephrons ,Proto-Oncogene Proteins c-met ,Mice, Mutant Strains ,Cell biology ,ErbB Receptors ,Mice, Inbred C57BL ,Endocrinology ,medicine.anatomical_structure ,Ureteric bud ,biology.protein ,Hepatocyte growth factor ,Female ,Development and Disease ,Ureter ,Developmental Biology ,medicine.drug ,Signal Transduction - Abstract
Ureteric bud (UB) branching during kidney development determines the final number of nephrons. Although hepatocyte growth factor and its receptor Met have been shown to stimulate branching morphogenesis in explanted embryonic kidneys, loss of Met expression is lethal during early embryogenesis without obvious kidney abnormalities. Metfl/fl;HoxB7-Cre mice,which lack Met expression selectively in the UB, were generated and found to have a reduction in final nephron number. These mice have increased Egf receptor expression in both the embryonic and adult kidney, and exogenous Egf can partially rescue the branching defect seen in kidney explants. Metfl/fl;HoxB7-Cre;wa-2/wa-2 mice, which lack normal Egfr and Met signaling, exhibit small kidneys with a marked decrease in UB branching at E14.5 as well as a reduction in final glomerular number. These mice developed progressive interstitial fibrosis surrounding collecting ducts with kidney failure and death by 3-4 weeks of age. Thus, in support of previous in vitro findings, Met and the Egf receptor can act cooperatively to regulate UB branching and mediate maintenance of the normal adult collecting duct.
- Published
- 2009